Preparation of compositions with essentially noncrystalline embedded macrolide antibiotics

• US 8,337,733 B2
• Filed: 08/14/2008
• Issued: 12/25/2012
• Est. Priority Date: 08/17/2007
• Status: Active Grant

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: Abbott GmbH & Company KG (Abbott Laboratories)
• Inventors: Westedt, Ulrich, Rosenberg, Jörg, Knobloch, Martin, Steiger, Norbert, Hach, Harald
• Primary Examiner(s): THROWER, LARRY W
• Application Number:
  US12/673,230
• Publication Number:
  US 20120001361A1
• Time in Patent Office: 1,594 Days
• Field of Search: 264/176.1
• US Class Current: 264/176.1
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: B29C 48/405 Intermeshing co-rotating screws
• CPC Class Codes: B29C 48/41 Intermeshing counter-rotating screws
• CPC Class Codes: B29C 48/57 provided with kneading disc-like elements, e.g. with oval-shaped elements
• CPC Class Codes: B29C 48/67 having incorporated mixing devices not provided for in groups B29C48/52 - B29C48/66

Abstract

A description is given of a process for the preparation of a pharmaceutical composition of a macrolide antibiotic in essentially noncrystalline form, in which the macrolide antibiotic, a water-swellable polymer and a proton donor are blended in an extruder in the presence of water and forced through a die, the ratio by weight of the sum of macrolide antibiotic, water-swellable polymer and proton donor to water being at least 1:1. The macrolide antibiotic is preferably clarithromycin and the water-swellable polymer is preferably chosen from crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose and crosslinked polyacrylic acid.

Claims

1. A process for the preparation of a pharmaceutical composition of a macrolide antibiotic in essentially noncrystalline form, comprising

mixing the macrolide antibiotic and a water-swellable polymer as a blend, wherein the mixing takes place in an extruder in the presence of water to obtain a mixture;

and

forcing the mixture through a die,

wherein said water-swellable polymer is selected from crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl-cellulose, and crosslinked polyacrylic acid,

provided that when the water-swellable polymer does not comprise crosslinked polyacrylic acid, the blend further comprises a proton donor that is mixed with the macrolide antibiotic and the water-swellable polymer;

wherein the ratio by weight of the blend to water is at least 1;

1.

2. The process as claimed in claim 1, wherein the macrolide antibiotic is present at 50% to 80% by weight of the blend.

3. The process as claimed in claim 2, wherein the macrolide antibiotic is present at 60% to 80% by weight of the blend.

4. The process as claimed in claim 1, wherein the macrolide antibiotic is present in molecular disperse form in the composition obtained.

5. The process as claimed in claim 1, wherein the macrolide antibiotic is present in amorphous form in the composition obtained.

6. The process as claimed in claim 1, wherein the macrolide antibiotic is selected from clarithromycin, roxithromycin, erythromycin and azithromycin.

7. The process as claimed in claim 6, wherein the macrolide antibiotic is clarithromycin.

8. The process as claimed in claim 1, wherein the water-swellable polymer has a water absorption capacity of at least 3.5 g of water/g of polymer.

9. The process as claimed in claim 1, wherein the proton donor is an organic acid.

10. The process as claimed in claim 9, wherein the organic acid is lactic acid, glycolic acid or citric acid.

11. The process as claimed in claim 9, wherein the organic acid is lactic acid.

12. The process as claimed in claim 1, wherein the ratio by weight of the blend to water is from 1:

1 to 2.7;

1.

13. The process as claimed in claim 1, wherein the water is added to the blend before the feeding of the blend to the extruder.

14. The process as claimed in claim 1, wherein the water is added to the blend at least partially in a conveying zone of the extruder.

15. The process as claimed in claim 1, wherein the mixture is extruded as a temperature in the range of between 40 and 80°

C.

16. The process as claimed in claim 1, in which the mixture is subjected to a vacuum before the die in order to at least partially remove the water.

17. The process as claimed in claim 1, wherein the ratio by weight of the blend to water is from 1.5:

1up to less than 1.9;

1, and the mixture is extruded at a temperature of 40°

C. or higher.

18. The process as claimed in claim 1, wherein the extruder is a multi-screw extruder.

19. The process as claimed in claim 1, wherein the ratio by weight of the blend to water is 1.9:

1 or greater, and the mixture is extruded at a temperature of 50°

C. or higher.